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Updated: Mar 17, 2026
High-throughput Quantitative Real-time RT-PCR Assay for Determining Expression Profiles of Types I and III Interferon Subtypes
Published on: March 24, 2015
Trisomy 21 consistently activates the interferon response
Kelly D Sullivan1,2,3,4, Hannah C Lewis1,2, Amanda A Hill1,2
1Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States.
Abstract:
Although it is clear that trisomy 21 causes Down syndrome, the molecular events acting downstream of the trisomy remain ill defined. Using complementary genomics analyses, we identified the interferon pathway as the major signaling cascade consistently activated by trisomy 21 in human cells. Transcriptome analysis revealed that trisomy 21 activates the interferon transcriptional response in fibroblast and lymphoblastoid cell lines, as well as circulating monocytes and T cells. Trisomy 21 cells show increased induction of interferon-stimulated genes and decreased expression of ribosomal proteins and translation factors. An shRNA screen determined that the interferon-activated kinases JAK1 and TYK2 suppress proliferation of trisomy 21 fibroblasts, and this defect is rescued by pharmacological JAK inhibition. Therefore, we propose that interferon activation, likely via increased gene dosage of the four interferon receptors encoded on chromosome 21, contributes to many of the clinical impacts of trisomy 21, and that interferon antagonists could have therapeutic benefits.
Insights
Trisomy 21 activates the interferon pathway in human cells, impacting gene expression and cell proliferation. This interferon activation may contribute to Down syndrome
Area of Science:
- Genetics
- Immunology
- Cell Biology
Background:
- Down syndrome is caused by trisomy 21, but the downstream molecular mechanisms are not fully understood.
- Identifying key signaling pathways affected by trisomy 21 is crucial for understanding Down syndrome pathogenesis.
Purpose of the Study:
- To identify the major signaling pathways activated by trisomy 21 in human cells.
- To investigate the functional consequences of trisomy 21-induced pathway activation on cell proliferation.
- To explore potential therapeutic targets for Down syndrome.
Main Methods:
- Complementary genomics analyses (transcriptome analysis, shRNA screen).
- Analysis of fibroblast, lymphoblastoid cell lines, monocytes, and T cells.
- Pharmacological inhibition of Janus kinases (JAKs).
Main Results:
- Trisomy 21 consistently activates the interferon pathway in various human cell types.
- Increased expression of interferon-stimulated genes and decreased expression of ribosomal proteins/translation factors observed.
- Interferon-activated kinases JAK1 and TYK2 suppress trisomy 21 fibroblast proliferation, which is reversible with JAK inhibition.
Conclusions:
- Interferon pathway activation, potentially due to increased gene dosage of interferon receptors on chromosome 21, contributes to Down syndrome clinical features.
- Interferon antagonists represent a potential therapeutic strategy for Down syndrome.
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